Tumor necrosis factor ␣ (TNF␣) is a pleiotropic cytokine involved in inflammatory responses which can trigger both cell apoptosis and cell activation. In antigen presenting cells (APC), TNF␣ increased antigen presentation, notably by up-regulation of HLA class II expression. In addition to their role in antigen presentation, HLA-DR molecules transduce intracellular signals which lead to cytokine up-regulation or cell death. We have previously observed that the susceptibility of APC to HLA-DR mediated apoptosis increase throughout their maturation. We therefore investigated the relationship between TNF␣ production and susceptibility to HLA-DR-mediated apoptosis of different APC. The hematopoietic progenitor cell line (KG1), monocytic cell line (THP-1), monocyte-derived dendritic cell (DC), and B-lymphoid cell line (Raji) have been studied. We report that apoptosis susceptibility and spontaneous TNF␣ release are correlated in these different cells. However, while autocrine TNF␣ production was critical for DC maturation, upregulation of TNF␣ release after HLA-DR crosslinking was not observed and neutralization of endogenous TNF␣ did not modify HLA-DR-mediated apoptosis. These data reveal that HLA-DR mediated apoptosis susceptibility and spontaneous TNF␣ release are regulated in a parallel manner and that while TNF␣ may induce maturation of APC to an "apoptosis sensitive" stage, there is no direct role for TNF␣ in HLA-DRmediated apoptosis of APC. Human Immunology 62, 106-112 (2001).